Pharmacological Treatment of Tremor in Parkinson's Disease Revisited

Abstract

The pathophysiology of Parkinson's disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological treatment. Levodopa is the most efficacious drug for most patients and should be used as primary approach to control troublesome tremor. While the efficacy of oral dopamine agonists on PD tremor has been demonstrated in controlled trials, there is no evidence of greater antitremor efficacy compared to levodopa. The magnitude of the antitremor effect of anticholinergics is generally lower than that of levodopa. Due to their adverse effects, anticholinergics have a limited role in selected young and cognitively intact patients. Propranolol may improve resting and action tremor and may be considered as an adjunct in patients with insufficient tremor response to levodopa and this also applies to clozapine, despite its unfavorable adverse effect profile. Treating motor fluctuations with MAO-B and COMT inhibitors, dopamine agonists, amantadine, or on-demand treatments such as subcutaneous or sublingual apomorphine and inhaled levodopa as well as with continuous infusions of levodopa or apomorphine will improve off period tremor episodes. For patients with drug-refractory PD tremor despite levodopa optimization deep brain stimulation and focused ultrasound are first-line considerations. Surgery can also be highly effective for the treatment medication-refractory tremor in selected patients without motor fluctuations. The present review highlights the clinical essentials of parkinsonian tremor, critically examines available trial data on the effects of medication and surgical approaches and provides guidance for the choice of treatments to control PD tremor in clinical practice.

Keywords: Parkinson’s disease; levodopa; levodopa-resistance; treatment; tremor.

Fig. 1

Anatomical regions (bold) involved in the pathogenesis of parkinsonian tremor. Distinctive changes in neurotransmission differentiating the tremor-dominant variant from other motor subtypes of Parkinson’s disease in italics. DA, dopamine; STN, subthalamic nucleus; VIM, ventral intermediate nucleus of the thalamus; SNpc, substantia nigra pars compacta; RRF, retrorubral field; GP, globus pallidus; 5-HT, serotonin; NE, norepinephrine; LC, locus coeruleus.

Fig. 2

Sequential treatment options in PD patients with insufficient tremor response to different baseline regimens. PD, Parkinson’s disease; ICD, impulse control disorders; L-dopa, levodopa; DA, dopamine; rx, risk; STN, subthalamic nucleus; DBS, deep brain stimulation; VIM, ventral intermediate nucleus of the thalamus; FUS, high-intensity focused ultrasound; pts, patients; motor compl., motor complications; inh., inhibitor; tx, treatment; MAO-B, monoamine oxidase B; COMT, catechol-O-methyl-transferase.

Fig. 3

Surgical options in-drug refractory PD tremor. *Age limit for STN DBS in patients with established motor complications 70–75 years. Note that VIM FUS in PD is usually performed unilaterally, resulting in unilateral tremor reduction in the contralateral hemibody. PD, Parkinson’s disease; rx, risk; STN, subthalamic nucleus; DBS, deep brain stimulation; GPi, globus pallidus interna; VIM, ventral intermediate nucleus of the thalamus; FUS, high-intensity focused ultrasound.